COLUMBUS was a randomized, Phase 3, multicenter, open-label, active-controlled trial8,9

Patients with locally advanced unresectable or metastatic melanoma

  • BRAF V600E and/or V600K
  • Untreated or progressed on/after immunotherapy in the adjuvant setting or first-line metastatic setting
  • ECOG PS 0 or 1
  • Prior use of BRAF or MEK inhibitors was prohibited
arrow

Randomization 1:1:1
N=577

arrows

COMBO 450 arm:
BRAFTOVI 450 mg QD + MEKTOVI 45 mg BID (n=192)

BRAFTOVI 300 arm:
BRAFTOVI 300 mg QD
(n=194)

vemurafenib arm:
vemurafenib 960 mg
BID (n=191)

Primary endpoint:
PFS by blinded independent central review (BRAFTOVI + MEKTOVI vs vemurafenib)

secondary endpoints: OS, ORR, and DoR across all arms by central and local review

BRAFTOVI and MEKTOVI have been studied in more than 4600 patients across multiple completed and ongoing oncology clinical trials6

View patient characteristics

Patients were stratified by AJCC stage (IIIB, IIIC, IVM1a or IVM1b, vs IVM1c), ECOG PS (0 or 1), and prior immunotherapy (yes or no).
Treatment was continued until disease progression or unacceptable toxicity.

AJCC, American Joint Committee on Cancer; BID, twice daily; DoR, duration of response;
ECOG PS, Eastern Cooperative Oncology Group performance status; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QD, once daily.

Primary endpoint:
PFS by blinded independent central review (BRAFTOVI + MEKTOVI vs vemurafenib)

secondary endpoints: OS, ORR, and DoR across all arms by central and local review

BRAFTOVI and MEKTOVI have been studied in more than 4600 patients across multiple completed and ongoing oncology clinical trials6

Longest observed median PFS of any BRAF + MEK inhibitor1-6

Median progression-free survival by central review at primary efficacy analysis*

14.9graphupdate03.27.19
Efficacy Results for COLUMBUS: Progression-free Survival
  BRAFTOVI + MEKTOVI
N=192
vemurafenib
N=191
Number of events (%) 98 (51) 106 (55)
Progressive disease 88 (46) 104 (54)
Death 10 (5) 2 (1)

*Median follow-up was 16.7 months.9

Category 1 Recommendation

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

National Comprehensive Cancer Network® (NCCN®) includes encorafenib (BRAFTOVI®) in combination with binimetinib (MEKTOVI®) as a first-line systemic therapy option for patients with metastatic or unresectable melanoma with a BRAF V600–activating mutation10,

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

COLUMBUS is the first and only study with a direct comparison of two different BRAF-inhibitor monotherapies7,9,†

Median progression-free survival as assessed by central review

DurationChart6

BRAFTOVI is approved in combination with MEKTOVI at the recommended starting dose of 450 mg. Please see Section 2 of the full Prescribing Information for both BRAFTOVI and MEKTOVI for complete information on dosage and administration. The analysis was pre-specified; however, it is descriptive in nature.

Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

An oral therapy for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E/K mutation1,2

The first BRAF + MEK inhibitor to demonstrate 33.6 months median OS1-7

Median overall survival by central review in the intent-to-treat population

33.6Graphupdate032719

The analysis of OS was pre-specified; however, the analysis is descriptive.

At 3 years, 47% overall survival was achieved

BRAFTOVI + MEKTOVI

1 year 2 year 3 year
76% 58% 47%
(95% CI: 69-81) (95% CI: 50-64) (95% CI: 39-54)

vemurafenib

1 year 2 year 3 year
63% 43% 32%
(95% CI: 56-70) (95% CI: 36-50) (95% CI: 25-39)

The analysis of OS was pre-specified; however, the analysis is descriptive.

High disease control rate was achieved with BRAFTOVI + MEKTOVI9

Disease control rates vs vemurafenib9

OverallBarGraph2c

CR, complete response; ORR, overall response rate; PR, partial response; SD, stable disease.

View dosing information for BRAFTOV + MEKTOVI

Learn more

BRAFTOVI + MEKTOVI may help your patients achieve a higher ORR1,2,9

Overall response rate by central review (secondary efficacy analysis)*

OverallBarGraph
CR and PR by central review

  • BRAFTOVI + MEKTOVI: 8% CR and
    55% PR
  • vemurafenib: 6% CR and 35% PR
CR and PR by local review

  • BRAFTOVI + MEKTOVI: 16% CR and
    59% PR
  • vemurafenib: 7% CR and 42% PR

*ORRs were assessed at the time of the primary PFS analysis.6

CR, complete response; ORR, overall response rate; PR, partial response.

BRAFTOVI + MEKTOVI was designed to inhibit the MAP-kinase pathway signaling

Learn more about MOA

BRAFTOVI + MEKTOVI delivered a DoR with a median of 16.6 months1,2,9

Duration of response by central review (secondary efficacy analysis)

DurationChart5

DoR, duration of response.

5% of patients permanently discontinued treatment due to adverse reactions1,2

The most common ARs resulting in permanent discontinuation were hemorrhage (2%) and headache (1%)1,2

Learn more about
safety profile

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNINGS AND PRECAUTIONS

New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuSCC/KA was 5.8 months. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. Assess LVEF by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients treated with MEKTOVI in combination with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

ADVERSE REACTIONS

The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), arthralgia (26%), myopathy (23%), hyperkeratosis (23%), rash (22%), headache (22%), constipation (22%), visual impairment (20%), serous retinopathy (20%). Other clinically important adverse reactions occurring in <10% of patients in the COLUMBUS Trial were facial paresis, pancreatitis, panniculitis, drug hypersensitivity and colitis.

In the COLUMBUS Trial, the most common laboratory abnormalities (all grades) (≥ 20%) included increased creatinine (93%), increased creatine phosphokinase (58%), increased gamma glutamyl transferase (GGT) (45%), anemia (36%), increased ALT (29%), hyperglycemia (28%), increased AST (27%), and increased alkaline phosphatase (21%).

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

DRUG INTERACTIONS

Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid coadministration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.

Indications and Usage

BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

IMPORTANT SAFETY INFORMATION AND INDICATION

WARNINGS AND PRECAUTIONS

New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuSCC/KA was 5.8 months. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI.

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. Assess LVEF by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely.

Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism.

Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and ≥ Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%).

Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients treated with MEKTOVI in combination with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings.

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD.

Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated.

Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated.

QTc Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms.

Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI.

Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended.

ADVERSE REACTIONS

The most common adverse reactions (≥20%, all Grades, in the COLUMBUS trial): were fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), arthralgia (26%), myopathy (23%), hyperkeratosis (23%), rash (22%), headache (22%), constipation (22%), visual impairment (20%), serous retinopathy (20%). Other clinically important adverse reactions occurring in <10% of patients in the COLUMBUS Trial were facial paresis, pancreatitis, panniculitis, drug hypersensitivity and colitis.

In the COLUMBUS Trial, the most common laboratory abnormalities (all grades) (≥ 20%) included increased creatinine (93%), increased creatine phosphokinase (58%), increased gamma glutamyl transferase (GGT) (45%), anemia (36%), increased ALT (29%), hyperglycemia (28%), increased AST (27%), and increased alkaline phosphatase (21%).

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

The information above applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

DRUG INTERACTIONS

Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Avoid coadministration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval.

Please see full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.

Indications and Usage

BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

References: 1. Braftovi® (encorafenib) Prescribing Information. Boulder, CO: Array BioPharma Inc, 01/19. 2. Mektovi® (binimetinib) Prescribing Information. Boulder, CO: Array BioPharma Inc, 01/19. 3. Long GV, Stroyakovskiy D, Gogas HJ, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. 4. Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30-39. 5. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. 6. Data on file. Array BioPharma, Inc. 7. Dummer R, Ascierto PA, Gogas HJ, et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. Published online September 12, 2018 doi:10.1016/S1470-2045(18)30497-2. 8. Lebbe C, Lorigan P, Ascierto P, et al. Treatment patterns and outcomes among patients diagnosed with unresectable stage III or IV melanoma in Europe: a retrospective, longitudinal survey (MELODY study). Eur J Cancer. 2012;48(17):3205-3214. 9. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2018;19(5)603-615. 10. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Cutaneous Melanoma V.1.2019. © National Comprehensive Cancer Network, Inc. 2018. All rights reserved. Accessed December 12, 2018. To view the most recent and complete version of the guideline, go online to NCCN.org. 11. Hall A, Meyle KD, Lange MK, et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E) BRAF oncogene. Oncotarget. 2013;4(4):585-599. 12. Delord JP, Robert C, Nyakas M, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23(18):5339-5348. 13. Koelblinger P, Thuerigen O, Dummer R. Development of encorafenib for BRAF-mutated advanced melanoma. Curr Opin Oncol. 2018;30(2):125-133. 14. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467(7315):596-599. 15. Tafinlar® (dabrafenib) Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp, 2018. 16. Mekinist® (trametinib) Prescribing Information. East Hanover, NJ: Novartis Pharmaceuticals Corp, 2018. 17. Cotellic® (cobimetinib) Prescribing Information. San Francisco, CA: Genentech, Inc, 2018. 18. Zelboraf® (vemurafenib) Prescribing Information. San Francisco, CA: Genentech, Inc, 2017.